Reprogramming rat astrocytes into neurons using small molecules for cell replacement following intracerebral hemorrhage

作     者：Yangyang Feng Shuang Bai Gaigai Li Hao Nie Shiling Chen Chao Pan Ping Zhang Yingxin Tang Na Liu Zhouping Tang 

作者机构：Department of NeurologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030HebeiChina 

出 版 物：《Brain Science Advances》 (神经科学（英文）)

年 卷 期：2021年第7卷第3期

页      面：184-198页

学科分类：1002[医学-临床医学] 100204[医学-神经病学] 10[医学] 

基　　金：funded by the National Natural Science Foundation of China(Grant Nos.82071330,81873750) the Science and Technology Plan Project of Wuhan,Hubei Province,China(Grant No.2018060401011316) the Natural Science Foundation of Hubei Province,China(Grant No.2019CFB113) 

主　　题：small-molecular compounds reprogramming astrocytes neurons regeneration intracerebral hemorrhage 

摘      要：Astrocytes are promising source cells to replace neurons lost to disease owing to a shared lineage and capacities for dedifferentiation and proliferation under pathological *** of astrocytes to neurons has been achieved by transcription factor modulation,but reprogramming in vitro or in vivo using small-molecule drugs may have several advantages for clinical *** instance,small molecules can be extensively characterized for efficacy,toxicity,and tumorigenicity in vitro;induce rapid initiation and subsequent reversal of transdifferentiation upon withdrawal,and obviate the need for exogenous gene *** we report a new astrocyte-neuron reprogramming strategy using a combination of small molecules(0.5 m M valproic acid,1μM Rep Sox,3μM CHIR99021,2μM I-BET151,10μM ISX-9,and 10μM forskolin).Treatment with this drug combination gradually reduced expression levels of astroglial marker proteins(glial fibrillary acidic protein and S100),transiently enhanced expression of the neuronal progenitor marker doublecortin,and subsequently elevated expression of the mature neuronal marker Neu N in primary astrocyte *** changes were accompanied by transition to a neuron-like morphological phenotype and expression of multiple neuronal transcription ***,this drug combination induced astrocyte-to-neuron transdifferentiation in a culture model of intracerebral hemorrhage(ICH)and upregulated many transdifferentiation-associated signaling molecules in ICH model *** culture,the drug combination also reduced ICH model-associated oxidative stress,apoptosis,and pro-inflammatory cytokine *** derived from small-molecule reprogramming of astrocytes in adult Sprague-Dawley rats demonstrated long-term survival and maintenance of neuronal *** small-molecule-induced astrocyte-to-neuron transdifferentiation method may be a promising strategy for neuronal replacement therapy.